Reactivation of herpesvirus infections is an increasing problem in patients with HIV. Reactivation of EBV replication is initially evidenced by increased shedding in the oropharynx and increased numbers of EBV- infected lymphocytes in the peripheral blood. In patients with HIV, replicating EBV is detected in the lesion of the tongue oral hairy leukoplakia and in lymphocytic interstitial pneumonitis (20, 34). Patients with HIV also have an increasing risk for development of EBV-positive lymphoma (45). The proposed studies are based on the premise that the increased risk of EBV-positive lymphoma is due to the increase in EBV replication potentially causing viremia resulting in the infection of additional lymphocytes. During this period of increased replication recombination and mutation results in the generation of strains which are essentially "escape mutants" as they harbor mutations in the epitopes recognized by the cytotoxic T cells. The proposed analyses will specifically: 1. Characterize in detail EBV infection in a closely followed group of patients. These studies will determine the state of viral infection, identify the viral genes which are expressed and identify the EBV strains present in the oropharynx serum and the peripheral blood lymphocytes. 2. Determine the pathogenic role of replication and EBV strain variation in patients who develop lymphoma through a retrospective analysis of samples obtained in the ACTG 204 study. An estimated 20-80 patients will develop lymphoma. The collected banked samples of plasma and leukocyte DNA from lymphoma patients and matched controls will be analyzed or evidence of replication in the peripheral blood and EBV strain variation. 3. Analyze EBV-positive lymphomas which develop in AIDS patients with regard to strain variation, viral expression and HLA type. 4. To further characterize EBV infection in patients with AIDS patients at UNC will be followed prospectively with collection and storage of throat washings serum and peripheral blood lymphocytes at enrollment and at 3 month intervals in patients with CD4+ cell counts of less than 50/mm(3). EBV-infected spontaneously transformed cells lines will be established from such patients. The HLA type and the EBV sequence of cytotoxic T-cell epitopes will be determined in these cell lines and the sensitivity of these lines to killing by HLA matched EBV-specific CTL lines will be assayed. These studies will determine the contribution of replication EBV strain variation, and escape from immune surveillance to lymphomagenesis.